Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor

ABSTRACT

The present invention relates to methods of treating or preventing a proliferative disease in a patient in need thereof by orally administering a therapeutically effective amount of an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof for at least two five-consecutive day cycle, wherein said compound is not administered to the patient for a period of about two days to about three days between said five-consecutive day cycles; the use of said compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease administered in accordance with said dosage regimen; therapeutic regimen comprising administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof in accordance with said dosage regimen; and related pharmaceutical compositions and packages thereof.

FIELD OF THE INVENTION

The present invention relates to methods of treating or preventing aproliferative disease in a patient in need thereof by orallyadministering a therapeutically effective amount of an alpha-isoformselective phosphatidylinositol 3-kinase inhibitor compound of formula(I) or a pharmaceutically acceptable salt thereof to the patient for atleast two five-consecutive day cycles, wherein said compound or apharmaceutically acceptable salt thereof is not administered to thepatient for a period of about two days to about three days between saidfive-consecutive day cycles; the use of said compound of formula (I) ora pharmaceutically acceptable salt thereof for the manufacture of amedicament for treating or preventing a proliferative diseaseadministered in accordance with said dosage regimen; therapeutic regimencomprising administration of said compound of formula (I) or apharmaceutically acceptable salt thereof in accordance with said dosageregimen; and related pharmaceutical compositions and packages thereof.

BACKGROUND OF THE INVENTION

Phosphatidylinositol 3-kinases (“PI-3 kinase” or “PI3K”) comprise afamily of lipid kinases that catalyze the transfer of phosphate to theD-3′ position of inositol lipids to produce phosphoinositol-3-phosphate(“PIP”), phosphoinositol-3,4-diphosphate (“PIP2”) andphosphoinositol-3,4,5-triphosphate (“PIP3”) that, in turn, act as secondmessengers in signaling cascades by docking proteins containingpleckstrin-homology, FYVE, Phox and other phospholipid-binding domainsinto a variety of signaling complexes often at the plasma membrane(Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al.,Annu. Rev. Cell Dev. Biol. 17:615 (2001)). Human cells contain threegenes (PIK3CA, PIK3CB and PIK3CD) encoding the catalytic p110 subunits(α, β, δ isoforms) of class IA PI3K enzymes. These catalytic p110α,p110β, and p110δ subunits are constitutively associated with aregulatory subunit that can be p85α, p55α, p50α, p85β or p55γ. p110α andp110β are expressed in most tissues. Class 1B PI3K has one familymember, a heterodimer composed of a catalytic p110γ subunit associatedwith one of two regulatory subunits, either the p101 or the p84 (Frumanet al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol.15:566 (2005)). The modular domains of the p85/55/50 subunits includeSrc Homology (SH2) domains that bind phosphotyrosine residues in aspecific sequence context on activated receptor and cytoplasmic tyrosinekinases, resulting in activation and localization of Class 1A PI3Ks.Class 1B, as well as p110β in some circumstances, is activated directlyby G protein-coupled receptors that bind a diverse repertoire of peptideand non-peptide ligands (Stephens et al., Cell 89:105 (1997)); Katso etal., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)). Consequently, theresultant phospholipid products of class I PI3K link upstream receptorswith downstream cellular activities including proliferation, survival,chemotaxis, cellular trafficking, motility, metabolism, inflammatory andallergic responses, transcription and translation (Cantley et al., Cell64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl etal., Cell 69:413 (1992)).

Aberrant regulation of PI3K, which often increases survival through Aktactivation, is one of the most prevalent events in human cancer and hasbeen shown to occur at multiple levels. The tumor suppressor gene PTEN,which dephosphorylates phosphoinositides at the 3′ position of theinositol ring and in so doing antagonizes PI3K activity, is functionallydeleted in a variety of tumors. In other tumors, the genes for the p110αisoform, PIK3CA, and for Akt are amplified and increased proteinexpression of their gene products has been demonstrated in several humancancers. Furthermore, mutations and translocation of p85α that serve toup-regulate the p85-p110 complex have been described in human cancers.Finally, somatic missense mutations in PIK3CA that activate downstreamsignaling pathways have been described at significant frequencies in awide diversity of human cancers, including 32% of colorectal cancers,27% of glioblastomas, 25% of gastric cancers, 36% of hepatocellularcarcinomas, and 18-40% of breast cancers. (Samuels et al., Cell Cycle3(10):1221 (2004); Hartmann et al, Acta Neuropathol., 109(6):639 (June2005); Li et al, BMC Cancer 5:29 (March 2005); Lee et al, Oncogene,24(8):1477 (2005); Backman et al, Cancer Biol. Ther. 3(8): 772-775(2004); Campbell et al., Cancer Research, 64(21): 7678-7681 (2004);Levine et al., Clin. Cancer Res., 11(8): 2875-2878 (2005); and Wu et al,Breast Cancer Res., 7(5):R609-R616 (2005)). Deregulation of PI3K,including the α-isoform, is one of the most common deregulationsassociated with human cancers and proliferative diseases (Parsons etal., Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc.4:988-1004 (2005)).

(S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide)is a specific 2-carboxamide cycloamino urea derivative compound thatpotently and selectively targets the alpha (α)-isoform of class IA PI3K.This compound has the following chemical structure:

(hereinafter, “compound of formula (I)” or “Compound A”). The compoundof formula (I) and pharmaceutically acceptable salts thereof, suitableformulations, and its method of preparation are described in PCTApplication WO2010/029082.

In a Phase I clinical trial, this alpha-isoform selective PI3K inhibitorcompound (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide)demonstrated clinical efficacy in the single-agent treatment of patientshaving advanced solid malignancies carrying an alteration in the PIK3CAgene. In the dose escalation phase, patients were orally administeredthis compound either (a) at a dosage ranging from 30 mg to 450 mg onceper day (q.d.) on a continuous daily schedule for 28-days, or (b) at adosage ranging from 120 mg to 200 mg twice per day (b.i.d.) on acontinuous daily schedule for 28-days, as guided by Bayesian logisticregression model with overdose control. After determination of themaximal tolerated dose (MTD), the dose expansion phase was conducted toadditionally treat patients having head and neck cancer with a PIK3CAalteration, patients having solid tumors with PIK3CA alteration, andpatients having PIK3CA wildtype ER+/HER2-breast cancer. Clinicalefficacy of this compound has been demonstrated preliminarily. As ofFeb. 15, 2013, confirmed partial responses have been observed in severalpatients treated at ≧270 mg/day, including patients suffering frombreast cancer (1 patient, confirmed), colorectal cancer (1 patientconfirmed), endometrial cancer (1 patient, confirmed) and cervicalcancer (1 patient confirmed). (Gonzalez-Angulo et al., “Safety,pharmacokinetics, and preliminary activity of the α-specific PI3Kinhibitor BYL719: results from the first-in-human study”, Presentationat the 2013 ASCO Annual Meeting, held May 31-Jun. 4, 2013 in Chicago,Ill.)

Despite the clinical efficacy of this compound in this Phase I clinicaltrial, some patients administered this compound on the once per day ortwice per day continuous daily schedule demonstrated at least one sideeffect or adverse event including, but not limited to, hyperglycemia(49% of patients), nausea (43% of patients), decreased appetite (34% ofpatients), diarrhea (35% of patients), rash and hypersensitivity (34% ofpatients), asthenia/fatigue (34% of patients), vomiting, stomatitis,dysgeusia, and/or dyspepsia. (Gonzalez-Angulo et al., Presentation atthe 2013 ASCO Annual Meeting, held May 31-Jun. 4, 2013 in Chicago, Ill.)

Currently, there is an unmet need for a potent alpha (α)-isoformselective PI3K inhibitor which can be administered to patients in adosage or dosage regimen that is clinically effective for treatment ofproliferative diseases, particularly cancer, but also that relieves,reduces, or alleviates the any known and unknown side effects (e.g, byseverity, occurrence rate, or frequency) of the drug. It is believedthat this has not been achieved for any alpha-isoform selective PI3Kinhibitor prior to the present invention.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating or preventing aproliferative disease in a patient in need thereof, comprising orallyadministering a therapeutically effective amount of the compound offormula (I):

or a pharmaceutically acceptable salt thereof to the patient in a dailydose of about 100 mg to about 450 mg for at least two five-consecutiveday cycles, wherein said compound or a pharmaceutically acceptable saltthereof is not administered to the patient for a period of about 2 daysto about 3 days between one five-consecutive day cycle and itssubsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to a method oftreating or preventing a proliferative disease comprising firstadministering to a patient in need thereof a compound of formula (I) ora pharmaceutically acceptable salt thereof in amount of about 100 mg toabout 450 mg daily on a continuous daily schedule via oraladministration, second determining said patient has a side effectselected from neutropenia, elevated bilirubin, cardiac toxicity,unstable angina, myocardial infarction, persistent hypertension,peripheral sensory or motor neuropathy/pain, hepatic dysfunction (e.g.,liver injury or liver disease, aspartate transaminase level elevation,alanine aminotransferase level elevation, etc.), reduced red and/orwhite blood cell count, hyperglycemia, nausea, decreased appetite,diarrhea, rash (e.g, maculopapular, acneiform, etc.) andhypersensitivity (e.g., increased sensitivity to bruise),photosensitivity, asthenia/fatigue, vomiting, stomatitis, oralmucositis, pancreatitis, dysgeusia, and dyspepsia after administrationof said compound of formula (I) or a pharmaceutically acceptable saltthereof to said patient, and third reducing the administration of saidcompound of formula (I) or a pharmaceutically acceptable salt thereof toa daily dose of about 100 mg to about 450 mg via oral administration forat least two five-consecutive day cycles, wherein said compound or apharmaceutically acceptable salt thereof is not administered to thepatient for a period of about 2 days to about 3 days between onefive-consecutive day cycle and its subsequent five-consecutive daycycle.

In a further embodiment, the present invention relates to a method ofreducing at least one side effect selected from neutropenia, elevatedbilirubin, cardiac toxicity, unstable angina, myocardial infarction,persistent hypertension, peripheral sensory or motor neuropathy/pain,hepatic dysfunction (e.g., liver injury or liver disease, aspartatetransaminase level elevation, alanine aminotransferase level elevation,etc.), reduced red and/or white blood cell count, hyperglycemia, nausea,decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.)and hypersensitivity (e.g., increased sensitivity to bruise),photosensitivity, asthenia/fatigue, vomiting, stomatitis, oralmucositis, pancreatitis, dysgeusia, and dyspepsia from prior treatmentwith the compound of formula (I) or a pharmaceutically acceptable saltthereof, comprising orally administering a therapeutically effectiveamount of the compound of formula (I) or a pharmaceutically acceptablesalt thereof to the patient in a daily dose of about 100 mg to about 450mg, preferably about 200 mg to about 400 mg or more preferably about 350mg to about 400 mg, for at least two five-consecutive day cycles,wherein said compound or a pharmaceutically acceptable salt thereof isnot administered to the patient for a period of about 2 days to about 3days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is orally administered toa patient in need thereof in a daily dose of about 100 mg to about 450mg of said compound of formula (I) or a pharmaceutically acceptable saltthereof for at least two five-consecutive day cycles, wherein saidmedicament is not administered to the patient for a period of about 2days to about 3 days between one five-consecutive day cycle and itssubsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor treating or preventing a proliferative disease, wherein saidcompound of formula (I) or a pharmaceutically acceptable salt thereof isorally administered to a patient in need thereof in a daily dose ofabout 100 mg to about 450 mg for at least two five-consecutive daycycles, wherein said compound of formula (I) or a pharmaceuticallyacceptable salt thereof is not administered to the patient for a periodof about 2 days to about 3 days between one five-consecutive day cycleand its subsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to apharmaceutical composition for use in the treatment or prevention of aproliferative disease in a patient in need thereof comprising an amountof about 100 mg to about 450 mg of a compound of formula (I) orpharmaceutically acceptable salt thereof together with one or morepharmaceutically acceptable excipients, wherein the pharmaceuticalcomposition is orally administered to a patient for at least twofive-consecutive day cycles and not administered to the patient for aperiod of about 2 days to about 3 days between one five-consecutive daycycle and its subsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to a therapeuticregimen comprising orally administering a therapeutically effectiveamount of the compound of formula (I) or a pharmaceutically acceptablesalt thereof to a patient in a daily dose of about 100 mg to about 450mg for at least two five-consecutive day cycles, wherein said compoundof formula (I) or a pharmaceutically acceptable salt thereof is notadministered to the patient for a period of about 2 days to about 3 daysbetween one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

In a further embodiment, the present invention relates to a packagecomprising a pharmaceutical composition comprising a compound of formula(I) or a pharmaceutically acceptable salt thereof in a daily dose ofabout 100 mg to about 450 mg together with one or more pharmaceuticallyacceptable excipients in combination with instructions to orallyadminister said pharmaceutical composition for at least twofive-consecutive day cycles and to not administered said composition fora period of about 2 days to about 3 days between one five-consecutiveday cycle and its subsequent five-consecutive day cycle.

DETAILED DESCRIPTION OF THE FIGURES

FIG. 1 shows concentration-time profiles after oral administration ofCompound A at 12.5, 25 and 50 mg/kg qd in nude mice (A) and at 12.5, 25,40 and 80 mg/kg qd in nude rats (B).

FIG. 2 shows observed versus predicted plasma concentrations after oraladministration of Compound A at 50 mg/kg qd in nude mice (A) and 40mg/kg qd in nude rats (B).

FIG. 3 shows observed versus predicted plasma concentrations after oraladministration of Compound A at 6.25, 12.5, 25 and 50 mg/kg qd in nudemice (A) and at 6.25, 12.5, 25, 40, 50 and 80 mg/kg qd in nude rats (B)on continuous daily schedule.

FIGS. 4A and 4B show observed versus predicted plasma concentrationsafter oral administration of Compound A at 40 mg/kg 2 qd on continuousdaily schedule in nude mice in the PK modeling study (A) and the laterrepeat confirmatory PK modeling study (B).

FIG. 5 shows the relationship between tumor tissue concentration andpercent S473P-Akt inhibition measured concomitantly in the Rat1-myrP110α tumors at different time points post-treatment with Compound A.

FIG. 6 shows the relationship between exposure, as measured by time overthe in vivo IC80 for S473P-Akt inhibition, and anti-tumor efficacy inRat1-myr P110α tumors treated with Compound A at 50 mg/kg qd.

FIG. 7 shows the relationship between the tumor PD marker (pAkt)response and antitumor efficacy observed in mice and rats treated orallyqd with various doses of Compound A.

FIG. 8 shows observed versus predicted tumor growth inhibition afteroral administration of Compound A from 6.25 to 70 mg/kg on continuousdaily schedule at various regimen in nude mice and rats.

FIG. 9 shows the relationship between plasma Compound A concentrationsand plasma insulin levels (A) or blood glucose levels (B) measured inthe same probe following Compound A treatment in nude mice.

FIG. 10 shows the relationship between plasma Compound A concentrationsand plasma insulin levels (A) or blood glucose levels (B) measured inthe same probe following Compound A treatment in nude rats.

FIG. 11 shows the correlation observed between the fraction of time overplasma hyperglycemia threshold between two consecutive dosing and bodyweight loss in nude mice and rats.

FIG. 12 shows a simulated efficacy curve as determined by the fractionof time above the IC₈₀ threshold for S473P-Akt and tolerability curve asdetermined by the duration of exposure above Compound A hyperglycemiathreshold in nude mice treated orally qd or 2 qd on continuous dailyschedule with increasing doses of Compound A.

FIG. 13 shows a simulated efficacy curve as determined by the fractionof time above the IC₈₀ threshold for S473P-Akt and tolerability curve asdetermined by the duration of exposure above Compound A hyperglycemiathreshold in nude rats treated orally qd or 2 qd with increasing dosesof Compound A.

FIG. 14 shows a simulated efficacy in Rat1-myr P110α tumor bearing nuderats treated orally with Compound A at 20 mg/kg in ALTERNATIVE SCHEDULE1 (A) or 14 mg/kg qd on continuous daily schedule (B).

FIG. 15 shows a simulated plasma PK profiles in nude rats treated orallywith Compound A at 20 mg/kg in ALTERNATIVE SCHEDULE 1, as defined inExample 1, or 14 mg/kg qd in continuous daily schedule.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of treating or preventing aproliferative disease in a patient in need thereof, comprising orallyadministering a therapeutically effective amount of the compound offormula (I), as defined herein, or a pharmaceutically acceptable saltthereof to the patient in a daily dose of about 100 mg to about 450 mgfor at least two five-consecutive day cycles, wherein said compound or apharmaceutically acceptable salt thereof is not administered to thepatient for a period of about two (2) days to about three (3) daysbetween one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

The general terms used herein are defined with the following meanings,unless explicitly stated otherwise:

The terms “comprising” and “including” are used herein in theiropen-ended and non-limiting sense unless otherwise noted.

The terms “a” and “an” and “the” and similar references in the contextof describing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

The term “a phosphatidylinositol 3-kinase inhibitor” or “PI3K inhibitor”is defined herein to refer to a compound which targets, decreases orinhibits activity of the phosphatidylinositol 3-kinase.

The term “pharmaceutically acceptable” is defined herein to refer tothose compounds, materials, compositions and/or dosage forms, which are,within the scope of sound medical judgment, suitable for contact withthe tissues a patient without excessive toxicity, irritation allergicresponse and other problem complications commensurate with a reasonablebenefit/risk ratio.

The term “treat”, “treating” or “treatment” as used herein comprises atreatment or therapeutic regimen relieving, reducing or alleviating atleast one symptom in a patient or effecting a delay of progression of aproliferative disorder. For example, treatment can be the diminishmentof one or several symptoms of a disorder or complete eradication of adisorder, such as cancer. Within the meaning of the present invention,the term “treat” also denotes to arrest, delay the onset (i.e., theperiod prior to clinical manifestation of a disorder) and/or reduce therisk of developing or worsening a disorder.

The term “prevent”, “preventing” or “prevention” as used hereincomprises the prevention of at least one symptom associated with orcaused by the state, disease or disorder being prevented.

The terms “clinically effective” or “therapeutically effective” is anobservable improvement over the baseline clinically observable signs andsymptoms of the state, disease or disorder treated with the therapeuticagent.

The term “therapeutically effective amount” is an amount sufficient toprovide an observable improvement over the baseline clinicallyobservable signs and symptoms of the state, disease or disorder treatedwith the therapeutic agent.

The term “pharmaceutical composition” is defined herein to refer to amixture or solution containing at least one therapeutic agent to beadministered to a patient, in order to prevent or treat a particulardisease or condition affecting the patient.

The phrase “five-consecutive day cycle” as used herein means thespecified therapeutic agent is administered to the patient during eachday for five-consecutive days and then not administered for a period oftime before the same therapeutic agent is next administered to thepatient. It is understood that the therapeutic agent may be administeredeach day in a single dosage unit or multiple dosage units and/oradministered each day in a single dose (once per day, q.d.) or divideddoses (more than once per day, e.g., twice per day, b.i.d.).

The phrase “continuous daily schedule” as used herein means thetherapeutic agent is administered to the patient during each day for atleast seven days or for an unspecified period of time or for as long astreatment is necessary. It is understood that the therapeutic agent maybe administered each day in a single dosage unit or multiple dosageunits and/or administered each day in a single dose (once per day, q.d.)or divided doses (more than once per day, e.g., twice per day, b.i.d.).

The term “day” as used herein refers to either one calendar day or one24-hour period.

The term “combination” is used herein to refer to either a fixedcombination in one dosage unit form, a non-fixed combination or a kit ofparts for the combined administration where the compound of formula (I)or a pharmaceutically acceptable salt thereof, and at least oneadditional therapeutic agent may be administered simultaneously,independently at the same time or separately within time intervals thatallow that the combination partners show a cooperative, e.g.,synergistic, effect. The term “fixed combination” means that thetherapeutic agents, e.g. the compound of formula (I) or apharmaceutically acceptable salt thereof and at least one additionaltherapeutic agent, are both administered to a patient simultaneously inthe form of a single entity or dosage unit. The term “non-fixedcombination” or “kit of parts” means that the therapeutic agents, e.g.the compound of formula (I) or a pharmaceutically acceptable saltthereof and at least one additional therapeutic agent, are bothadministered to a patient as separate entities or dosage units eithersimultaneously, concurrently or sequentially with no specific timelimits, wherein such administration provides therapeutically effectivelevels of the two therapeutic agents in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more therapeutic agents.

The term “combined administration” as used herein is defined toencompass the administration of the selected therapeutic agents to asingle patient, and are intended to include treatment regimens in whichthe agents are not necessarily administered by the same route ofadministration or at the same time.

The terms “patient”, “subject” or “warm-blooded animal” is intended toinclude animals. Examples of subjects include mammals, e.g., humans,dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, andtransgenic non-human animals. In certain embodiments, the subject is ahuman, e.g., a human suffering from, at risk of suffering from, orpotentially capable of suffering from a brain tumor disease.Particularly preferred, the patient or warm-blooded animal is human.

The terms “about” or “approximately” usually mean within 10%, morepreferably within 5%, of a given value or range.

WO2010/029082 describes specific 2-carboxamide cycloamino ureaderivatives, which have been found to have highly selective inhibitoryactivity for the alpha-isoform of phosphatidylinositol 3-kinase (PI3K).The alpha-isoform selective PI3K inhibitor suitable for the presentinvention is a compound having the following formula (I):

(hereinafter “compound of formula (I)” or “Compound A”) orpharmaceutically acceptable salts thereof. The compound of formula (I)is also known as the chemical compound (S)-Pyrrolidine-1, 2-dicarboxylicacid 2-amide1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide).The compound of formula (I), its pharmaceutically acceptable salts andsuitable formulations are described in PCT Application No.WO2010/029082, which is hereby incorporated by reference in itsentirety, and methods of its preparation have been described, forexample, in Example 15 therein.

As used herein, the term “salts” (including “or salts thereof” or “or asalt thereof”), can be present alone or in mixture with free compound offormula (I) and are preferably pharmaceutically acceptable salts. Suchsalts are formed, for example, as acid addition salts, preferably withorganic or inorganic acids, from the compound of formula (I) with abasic nitrogen atom, especially the pharmaceutically acceptable salts.Suitable in-organic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, e.g., carboxylic acids or sulfonic acids, such as fumaricacid or methansulfonic acid. For isolation or purification purposes itis also possible to use pharmaceutically unacceptable salts, for examplepicrates or perchlorates. For therapeutic use, only pharmaceuticallyacceptable salts or free compound are employed (where applicable in theform of pharmaceutical preparations), and these are therefore preferred.In view of the close relationship between the compound of formula (I) infree form and those in the form of its salts, any reference to the freecompound hereinbefore and hereinafter is to be understood as referringalso to the corresponding salts, as appropriate and expedient. The saltsof compound of the formula (I) are preferably pharmaceuticallyacceptable salts; suitable counter-ions forming pharmaceuticallyacceptable salts are known in the field.

The compound of formula (I) has been previously demonstrated to potentlyand selectively inhibit the alpha-isoform of the PI3K, including forexample, Examples A and C of PCT Application No. WO2010/029082. Incontrast to prior known PI3K inhibitors, the compound of formula (I)inhibits the alpha-isoform of PI3K (IC₅₀ of 0.008 μmol/L) more potentlythan the beta-isoform (IC₅₀ of 1.212 μmol/L), delta-isoform (IC₅₀ of0.077 μmol/L), and gamma-isoform (IC₅₀ of 1.097 μmol/L) in cellularassays and lacks inhibitory activity against the Vps34, mTOR, DNA-PK andATR. Further, the compound of formula (I) shows inhibitory activityagainst the wildtype alpha-isoform of PI3K, E545K mutant alpha-isoformof PI3K, and H1047R mutant alpha-isoform of PI3K.

The compound of formula (I) or its pharmaceutically acceptable salts maybe orally administered at a dosage of about 100 mg to about 450 mg perday to a human patient in need thereof. The term “daily dose” refers tothe total dosage amount of the therapeutic agent administered to aspecific patient in any single day. In further embodiments, the compoundof formula (I) may be administered to patient at a daily dose of about200 to about 400 mg per day, or about 240 mg to about 400 mg per day, orabout 300 mg to about 400 mg per day, or about 350 mg to about 400 mgper day. In a preferred embodiment, the compound of formula (I) isadministered to a human patient at a daily dose of about 350 mg to about400 mg per day.

The daily dose may be administered to the patient in single dose (onceper day, q.d.) or divided doses (more than once per day, e.g., twice perday, b.i.d.). In one embodiment, the daily dose is administered in aonce per day (q.d.). In a further embodiment, the daily dose isadministered twice per day (b.i.d.)

The daily dose may be administered to the patient in a single dosageunit or amounts of multiple dosage units to make up the daily dose.

In accordance with the dosage regimen of the present invention, thecompound of formula (I) or a pharmaceutically acceptable salt thereof isorally administered to a patient in need thereof in a daily dose ofabout 100 mg to about 450 mg for at least two five-consecutive daycycles, wherein said compound or a pharmaceutically acceptable saltthereof is not administered to the patient for a period of about 2 daysto about 3 days between one five-consecutive day cycle and itssubsequent five-consecutive day cycle. Preferably, the compound or apharmaceutically acceptable salt thereof is not administered for about 2days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

In one embodiment, the compound of formula (I) or a pharmaceuticallyacceptable salt thereof is orally administered to a patient in needthereof once per day (q.d.) at a daily dose of about 100 mg to about 450mg, preferably about 350 mg to about 400 mg, for at least twofive-consecutive day cycles, wherein said compound or a pharmaceuticallyacceptable salt thereof is not administered to the patient for a periodof about 2 days to about 3 days between one five-consecutive day cycleand its subsequent five-consecutive day cycle.

In a further embodiment, the compound of formula (I) or apharmaceutically acceptable salt thereof is orally administered to apatient in need thereof twice per day (b.i.d.) at a daily dose of about100 mg to about 450 mg, preferably about 350 mg to about 400 mg, for atleast two five-consecutive day cycles, wherein said compound or apharmaceutically acceptable salt thereof is not administered to thepatient for a period of about 2 days to about 3 days between onefive-consecutive day cycle and its subsequent five-consecutive daycycle.

It is understood that the dosage regimen of the present invention may bealternatively defined relative to timing of the actual administrationsof the compound of formula (I) or its pharmaceutically acceptable salt.

In one embodiment, the compound of formula (I) or a pharmaceuticallyacceptable salt thereof is orally administered to a patient in needthereof once per day (q.d.) at a daily dose of about 100 mg to about 450mg, preferably about 350 mg to about 400 mg, for at least twofive-consecutive day cycles, wherein said compound or a pharmaceuticallyacceptable salt thereof is not administered to the patient for a periodof about 3 days between the last administration of said compound or apharmaceutically acceptable salt thereof in one five-consecutive daycycle and the first administration of said compound or apharmaceutically acceptable salt thereof in its subsequentfive-consecutive day cycle.

In a further embodiment, the compound of formula (I) or apharmaceutically acceptable salt thereof is orally administered to apatient in need thereof twice per day (b.i.d.) at a daily dose of about100 mg to about 450 mg, preferably about 350 mg to about 400 mg, for atleast two five-consecutive day cycles, wherein said compound or apharmaceutically acceptable salt thereof is not administered for aperiod of about 2.5 days between the last administration of saidcompound or a pharmaceutically acceptable salt thereof in onefive-consecutive day cycle and the first administration of said compoundor a pharmaceutically acceptable salt thereof in its subsequentfive-consecutive day cycle.

Proliferative diseases that may be treated or prevented by theadministration of the compound of formula (I) or a pharmaceuticallyacceptable in accordance with the dosage regimen of the presentinvention are particularly those mediated by the alpha-isoform of thePI3K. It is understood that one embodiment of the present inventionincludes the treatment of the proliferative disease and that a furtherembodiment of the present invention includes the prevention of theproliferative disease.

Examples of proliferative diseases which may be treated or prevented inaccordance with the present invention include, cancer, polycythemiavera, essential thrombocythemia, myelofibrosis with myeloid metaplasia,asthma, COPD, ARDS, Loffler's syndrome, eosinophilic pneumonia,parasitic (in particular metazoan) infestation (including tropicaleosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa(including Churg-Strauss syndrome), eosinophilic granuloma,eosinophil-related disorders affecting the airways occasioned bydrug-reaction, psoriasis, contact dermatitis, atopic dermatitis,alopecia areata, erythema multiforme, dermatitis herpetiformis,scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullouspemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosaacquisita, autoimmune haematogical disorders (e.g. haemolytic anaemia,aplastic anaemia, pure red cell anaemia and idiopathicthrombocytopenia), systemic lupus erythematosus, polychondritis,scleroderma, Wegener granulomatosis, dermatomyositis, chronic activehepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue,autoimmune inflammatory bowel disease (e.g. ulcerative colitis andCrohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis,cardiovascular diseases, atherosclerosis, hypertension, deep venousthrombosis, stroke, myocardial infarction, unstable angina,thromboembolism, pulmonary embolism, thrombolytic diseases, acutearterial ischemia, peripheral thrombotic occlusions, and coronary arterydisease, reperfusion injuries, retinopathy, such as diabetic retinopathyor hyperbaric oxygen-induced retinopathy, and conditions characterizedby elevated intraocular pressure or secretion of ocular aqueous humor,such as glaucoma.

Preferably, the proliferative disease is a cancer. The term “cancer”refers to tumors and/or cancerous cell growth preferably mediated by thealpha-isoform of the PI3K. In particular, the compounds are useful inthe treatment of cancers including, for example, sarcoma, lung,bronchus, prostate, breast (including sporadic breast cancers andsufferers of Cowden disease), pancreas, gastrointestine, colon, rectum,colon carcinoma, colorectal adenoma, thyroid, liver, intrahepatic bileduct, hepatocellular, adrenal gland, stomach, gastric, glioma,glioblastoma, endometrial, melanoma, kidney, renal pelvis, urinarybladder, uterine corpus, uterine cervix, vagina, ovary, multiplemyeloma, esophagus, a leukemia, acute myelogenous leukemia, chronicmyelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain,oral cavity and pharynx, larynx, small intestine, non-Hodgkin lymphoma,melanoma, villous colon adenoma, a neoplasia, a neoplasia of epithelialcharacter, lymphomas, a mammary carcinoma, basal cell carcinoma,squamous cell carcinoma, actinic keratosis, head and neck, polycythemiavera, essential thrombocythemia, myelofibrosis with myeloid metaplasia,and Waldenstroem disease.

Proliferative diseases mediated by the alpha-subunit of PI3K may includethose showing overexpression or amplification of PI3K alpha, somaticmutation of PIK3CA or germline mutations or somatic mutation of PTEN ormutations and translocation of p85α that serve to up-regulate thep85-p110 complex. In a preferred embodiment, the cancer is a tumorand/or cancerous growth mediated by the alpha isoform of PI3K.

In one embodiment, the proliferative disease is a cancer selected from acancer of the lung, bronchus, prostate, breast (including sporadicbreast cancers and sufferers of Cowden disease), colon, rectum, coloncarcinoma, colorectal adenoma, pancreas, gastrointestine,hepatocellular, stomach, gastric, ovary, squamous cell carcinoma, andhead and neck.

In a further embodiment, the proliferative disease is a cancer selectedfrom a cancer of the breast, colon, rectum, colon carcinoma, colorectaladenoma, endometrial, and cervical.

In a further embodiment, the proliferative disease is a cancer selectedfrom a cancer of the lung, breast (including sporadic breast cancers andsufferers of Cowden disease), gastric, ovary and head and neck.

In a further embodiment, the present invention relates to the treatmentof a cancer by the administration of the compound of formula (I) or apharmaceutically acceptable in accordance with the dosage regimen of thepresent invention.

It is believed that reducing the dosing of this potent alpha-isoformselective PI3K inhibitor compound of formula (I) or a pharmaceuticallyacceptable salt thereof from oral administration at (a) a daily dose ofabout 100 mg to about 450 mg daily on a continuous daily schedule to (b)a daily dose of about 100 mg to about 450 mg for at least twofive-consecutive day cycles, wherein said compound is not administeredfor a period of about 2 days to about 3 days between saidfive-consecutive day cycles, is effective to treat or prevent aproliferative disease while relieving, reducing, or alleviating theseverity, occurrence rate and/or frequency of any side effects. This isparticularly applicable to treatment or prevention of a cancer.

Examples of such side effects which may relieved, reduced, or alleviatedby the dosage regimen of the present invention include, but are notlimited to, neutropenia, elevated bilirubin, cardiac toxicity, unstableangina, myocardial infarction, persistent hypertension, peripheralsensory or motor neuropathy/pain, hepatic dysfunction (e.g., liverinjury or liver disease, aspartate transaminase level elevation, alanineaminotransferase level elevation, etc.), reduced red and/or white bloodcell count, hyperglycemia, nausea, decreased appetite, diarrhea, rash(e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g.,increased sensitivity to bruise), photosensitivity, asthenia/fatigue,vomiting, stomatitis, oral mucositis, pancreatitis, dysgeusia, anddyspepsia. It is understood by one of ordinary skill in the art how toassess such side effects in a patient suffering from proliferativediseases using one's experience or prior knowledge and/or by referencingstandard side effect grading criteria, for example, by assessing suchpatient using the NCI Common Terminology Criteria for Adverse Events,version 4.03 (website located at:http://evs.nci.nih.gov/ftp1/CTCAE/About.html), which is herebyincorporated by reference in its entirety.

In a preferred embodiment, the side effect relieved, reduced, oralleviated by the dosage regimen of the present invention is a conditionselected from hyperglycemia, nausea, decreased appetite, diarrhea, rash(e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g.,increased sensitivity to bruise), photosensitivity, asthenia/fatigue,vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia. Morepreferably, the side effect relieved, reduced, or alleviated by thedosage regimen of the present invention is hyperglycemia.

It can be shown by established test models that the dosage regimen ofthe present invention results in the beneficial effects described hereinbefore. The person skilled in the art is fully enabled to select arelevant test model to prove such beneficial effects. Thepharmacological activity of the compound of formula (I) or itspharmaceutically acceptable salt may, for example, be demonstrated in aclinical study, an animal study or in a test procedure as essentiallydescribed hereinafter.

Suitable clinical studies are in particular, for example, open label,dose escalation studies in patients with a proliferative disease,including for example a tumor disease, e.g., breast cancer, wherein saidpatients are orally administered the compound of formula (I) inaccordance with the dosage regimen of the present invention. Preferably,patients are assigned to different groups wherein at least one group isadministered the compound of formula (I) on a continuous daily scheduleand at least one group is administered the compound of formula (I) inaccordance with the dosage regimen of the present invention. Suchstudies prove in particular the efficacy of the therapeutic agent andits impact on existing or potential side effects. The beneficial effectson a proliferative disease may be determined directly through theresults of these studies which are known as such to a person skilled inthe art. Such studies may be, in particular, suitable to compare theeffects of a continuous daily schedule using the therapeutic agents andthe dosing schedule of the present invention. Each patient may receivedoses of the compound of formula (I) or its pharmaceutically acceptablesalt either once per day or more than once (e.g., twice) per day. Theefficacy of the treatment may be determined in such studies, e.g., after12, 18 or 24 weeks by evaluation of symptom scores and/or tumor sizemeasurements every 6 weeks.

In accordance with the present invention, the compound of formula (I) ora pharmaceutically acceptable salt thereof is preferably used oradministered in the form of pharmaceutically compositions that contain atherapeutically effective amount of the compound of formula (I) orpharmaceutically acceptable salt thereof together with one or morepharmaceutically acceptable excipients suitable for oral administration.The pharmaceutical composition may comprise an amount of about 100 mg toabout 450 mg of a compound of formula (I) or pharmaceutically acceptablesalt thereof to be administered in a single dosage unit. Alternatively,the pharmaceutical composition may comprise an amount of the compound offormula (I) or pharmaceutically acceptable salt thereof which issubdivided into multiple dosage units and administered for a dailydosage of about 100 mg to about 450 mg of the compound of formula (I) orpharmaceutically acceptable salt thereof.

The pharmaceutical compositions used according to the present inventioncan be prepared in a manner known per se to be suitable for oraladministration to mammals (warm-blooded animals), including humans.Pharmaceutical compositions for oral administration may include, forexample, those in dosage unit forms, such as sugar-coated tablets,tablets, capsules, sachets and furthermore ampoules. If not indicatedotherwise, these are prepared in a manner known per se, for example bymeans of conventional mixing, granulating, sugar-coating, dissolving orlyophilizing processes. It will be appreciated that the amount of theactive ingredient contained in an individual dose or dosage unit neednot in itself constitute a therapeutically effective amount since thenecessary effective amount can be reached by administration of aplurality of dosage units.

The novel pharmaceutical composition may contain, for example, fromabout 10% to about 100%, preferably from about 20% to about 60%, of theactive ingredient.

In preparing the compositions for oral dosage unit form, any of theusual pharmaceutically acceptable excipients may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents; or excipients such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents and the like in the case of oral solidpreparations such as, for example, powders, capsules and tablets, withthe solid oral preparations being preferred over the liquidpreparations. Because of their ease of administration, tablets andcapsules represent the most advantageous oral dosage unit form in whichcase solid pharmaceutical carriers are obviously employed.

One of ordinary skill in the art may select one or more of theaforementioned excipients with respect to the particular desiredproperties of the dosage unit form by routine experimentation andwithout any undue burden. The amount of each excipient used may varywithin ranges conventional in the art. The following references whichare all hereby incorporated by reference disclose techniques andexcipients used to formulate oral dosage forms. (See The Handbook ofPharmaceutical Excipients, 4th edition, Rowe et al., Eds., AmericanPharmaceuticals Association (2003); and Remington: the Science andPractice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams &Wilkins (2003).)

Examples of pharmaceutically acceptable disintegrants include, but arenot limited to, starches; clays; celluloses; alginates; gums;cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone orcrospovidone, e.g., POLYPLASDONE XL from International SpecialtyProducts (Wayne, N.J.); cross-linked sodium carboxymethylcellulose orcroscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linkedcalcium carboxymethylcellulose; soy polysaccharides; and guar gum. Thedisintegrant may be present in an amount from about 0% to about 10% byweight of the composition. In one embodiment, the disintegrant ispresent in an amount from about 0.1% to about 5% by weight ofcomposition.

Examples of pharmaceutically acceptable binders include, but are notlimited to, starches; celluloses and derivatives thereof, for example,microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia,Pa.), hydroxypropyl cellulose hydroxylethyl cellulose andhydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp.(Midland, Mich.); sucrose; dextrose; corn syrup; polysaccharides; andgelatin. The binder may be present in an amount from about 0% to about50%, e.g., 2-20% by weight of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceuticallyacceptable glidants include, but are not limited to, colloidal silica,magnesium trisilicate, starches, talc, tribasic calcium phosphate,magnesium stearate, aluminum stearate, calcium stearate, magnesiumcarbonate, magnesium oxide, polyethylene glycol, powdered cellulose andmicrocrystalline cellulose. The lubricant may be present in an amountfrom about 0% to about 10% by weight of the composition. In oneembodiment, the lubricant may be present in an amount from about 0.1% toabout 1.5% by weight of composition. The glidant may be present in anamount from about 0.1% to about 10% by weight.

Examples of pharmaceutically acceptable fillers and pharmaceuticallyacceptable diluents include, but are not limited to, confectioner'ssugar, compressible sugar, dextrates, dextrin, dextrose, lactose,mannitol, microcrystalline cellulose, powdered cellulose, sorbitol,sucrose and talc. The filler and/or diluent, e.g., may be present in anamount from about 0% to about 80% by weight of the composition.

A dosage unit form containing the compound of formula (I) or apharmaceutically acceptable salt thereof may be in the form ofmicro-tablets enclosed inside a capsule, e.g. a gelatin capsule. Forthis, a gelatin capsule as is employed in pharmaceutical formulationscan be used, such as the hard gelatin capsule known as CAPSUGEL,available from Pfizer.

Examples of pharmaceutically acceptable disintegrants include, but arenot limited to, starches; clays; celluloses; alginates; gums;cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone orcrospovidone, e.g., POLYPLASDONE XL from International SpecialtyProducts (Wayne, N.J.); cross-linked sodium carboxymethylcellulose orcroscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linkedcalcium carboxymethylcellulose; soy polysaccharides; and guar gum. Thedisintegrant may be present in an amount from about 0% to about 10% byweight of the composition. In one embodiment, the disintegrant ispresent in an amount from about 0.1% to about 5% by weight ofcomposition.

Examples of pharmaceutically acceptable binders include, but are notlimited to, starches; celluloses and derivatives thereof, for example,microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia,Pa.), hydroxypropyl cellulose hydroxylethyl cellulose andhydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp.(Midland, Mich.); sucrose; dextrose; corn syrup; polysaccharides; andgelatin. The binder may be present in an amount from about 0% to about50%, e.g., 2-20% by weight of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceuticallyacceptable glidants include, but are not limited to, colloidal silica,magnesium trisilicate, starches, talc, tribasic calcium phosphate,magnesium stearate, aluminum stearate, calcium stearate, magnesiumcarbonate, magnesium oxide, polyethylene glycol, powdered cellulose,Sodium stearyl fumarate and microcrystalline cellulose. The lubricantmay be present in an amount from about 0% to about 10% by weight of thecomposition. In one embodiment, the lubricant may be present in anamount from about 0.1% to about 1.5% by weight of composition. Theglidant may be present in an amount from about 0.1% to about 10% byweight.

Examples of pharmaceutically acceptable fillers and pharmaceuticallyacceptable diluents include, but are not limited to, confectioner'ssugar, compressible sugar, dextrates, dextrin, dextrose, lactose,mannitol, microcrystalline cellulose, powdered cellulose, sorbitol,sucrose and talc. The filler and/or diluent, e.g., may be present in anamount from about 0% to about 80% by weight of the composition.

In one embodiment, the present invention relates to a pharmaceuticalcomposition for use in the treatment or prevention of a proliferativedisease in a patient in need thereof comprising an amount of about 100mg to about 450 mg of a compound of formula (I) or pharmaceuticallyacceptable salt thereof together with one or more pharmaceuticallyacceptable excipients, wherein the pharmaceutical composition is orallyadministered to a patient for at least two five-consecutive day cyclesand not administered to the patient for a period of about 2 days toabout 3 days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

In one embodiment, the present invention relates to a method of treatingor preventing a proliferative disease in a patient in need thereof,comprising orally administering a therapeutically effective amount ofthe compound of formula (I) or a pharmaceutically acceptable saltthereof to the patient in a daily dose of about 100 mg to about 450 mg,preferably about 200 mg to about 400 mg or more preferably about 350 mgto about 400 mg, for at least two five-consecutive day cycles, whereinsaid compound or a pharmaceutically acceptable salt thereof is notadministered to the patient for a period of about 2 days to about 3 daysbetween one five-consecutive day cycle and its subsequentfive-consecutive day cycle. Preferably, the compound or apharmaceutically acceptable salt thereof is not administered for about 2days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

In a further embodiment, the present invention relates to a method oftreating or preventing a proliferative disease in a patient in needthereof, comprising orally administering a therapeutically effectiveamount of the compound of formula (I) or a pharmaceutically acceptablesalt thereof to the patient once per day (q.d.) at a daily dose of about100 mg to about 450 mg for at least two five-consecutive day cycles,wherein said compound or a pharmaceutically acceptable salt thereof isnot administered to the patient for a period of about 2 days to about 3days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

In a further embodiment, the present invention relates to a method oftreating or preventing a proliferative disease in a patient in needthereof, comprising orally administering a therapeutically effectiveamount of the compound of formula (I) or a pharmaceutically acceptablesalt thereof to the patient twice per day (b.i.d.) at a daily dose ofabout 100 mg to about 450 mg for at least two five-consecutive daycycles, wherein said compound or a pharmaceutically acceptable saltthereof is not administered to the patient for a period of about 2 daysto about 3 days between one five-consecutive day cycle and itssubsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to a method oftreating or preventing a proliferative disease in a patient in needthereof, comprising orally administering a therapeutically effectiveamount of the compound of formula (I) or a pharmaceutically acceptablesalt thereof to the patient once per day (q.d.) at a daily dose of about100 mg to about 450 mg for at least two five-consecutive day cycles,wherein said compound or a pharmaceutically acceptable salt thereof isnot administered to the patient for a period of about 3 days between thelast administration of said compound or a pharmaceutically acceptablesalt thereof in one five-consecutive day cycle and the firstadministration of said compound or a pharmaceutically acceptable saltthereof in its subsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to a method oftreating or preventing a proliferative disease in a patient in needthereof, comprising orally administering a therapeutically effectiveamount of the compound of formula (I) or a pharmaceutically acceptablesalt thereof to the patient twice per day (b.i.d.) at a daily dose ofabout 100 mg to about 450 mg, preferably about 350 mg to about 400 mg,for at least two five-consecutive day cycles, wherein said compound or apharmaceutically acceptable salt thereof is not administered for aperiod of about 2.5 days between the last administration of saidcompound or a pharmaceutically acceptable salt thereof in onefive-consecutive day cycle and the first administration of said compoundor a pharmaceutically acceptable salt thereof in its subsequentfive-consecutive day cycle.

In a further embodiment, the present invention relates to a method oftreating or preventing a proliferative disease in accordance with thedosage regimen herein, wherein the compound of formula (I) or itspharmaceutically acceptable salt thereof is administered in two or moreof said five-consecutive day cycles until the relief, reduction, oralleviation of the severity, occurrence rate, or frequency of at leastone side effect in said patient.

In a further embodiment, the present invention relates to a method oftreating or preventing a proliferative disease in accordance with thedosage regimen herein, wherein the compound of formula (I) or itspharmaceutically acceptable salt thereof is administered in two or moreof said five-consecutive day cycle until the progression of the disease.

In a further embodiment, the present invention relates to a method oftreating or preventing a proliferative disease comprising firstadministering to a patient in need thereof a compound of formula (I) ora pharmaceutically acceptable salt thereof in amount of about 100 mg toabout 450 mg daily on a continuous daily schedule via oraladministration, second determining said patient has a side effectselected from neutropenia, elevated bilirubin, cardiac toxicity,unstable angina, myocardial infarction, persistent hypertension,peripheral sensory or motor neuropathy/pain, hepatic dysfunction (e.g.,liver injury or liver disease, aspartate transaminase level elevation,alanine aminotransferase level elevation, etc.), reduced red and/orwhite blood cell count, hyperglycemia, nausea, decreased appetite,diarrhea, rash (e.g, maculopapular, acneiform, etc.) andhypersensitivity (e.g., increased sensitivity to bruise),photosensitivity, asthenia/fatigue, vomiting, stomatitis, oralmucositis, pancreatitis, dysgeusia, and dyspepsia after administrationof said compound of formula (I) or a pharmaceutically acceptable saltthereof to said patient, and third reducing the administration of saidcompound of formula (I) or a pharmaceutically acceptable salt thereof toa daily dose of about 100 mg to about 450 mg via oral administration forat least two five-consecutive day cycles, wherein said compound or apharmaceutically acceptable salt thereof is not administered to thepatient for a period of about 2 days to about 3 days between onefive-consecutive day cycle and its subsequent five-consecutive daycycle.

In a further embodiment, the present invention relates to a method ofreducing at least one side effect selected from neutropenia, elevatedbilirubin, cardiac toxicity, unstable angina, myocardial infarction,persistent hypertension, peripheral sensory or motor neuropathy/pain,hepatic dysfunction (e.g., liver injury or liver disease, aspartatetransaminase level elevation, alanine aminotransferase level elevation,etc.), reduced red and/or white blood cell count, hyperglycemia, nausea,decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.)and hypersensitivity (e.g., increased sensitivity to bruise),photosensitivity, asthenia/fatigue, vomiting, stomatitis, oralmucositis, pancreatitis, dysgeusia, and dyspepsia from prior treatmentwith the compound of formula (I) or a pharmaceutically acceptable saltthereof, comprising orally administering a therapeutically effectiveamount of the compound of formula (I) or a pharmaceutically acceptablesalt thereof to the patient in a daily dose of about 100 mg to about 450mg, preferably about 200 mg to about 400 mg or more preferably about 350mg to about 400 mg, for at least two five-consecutive day cycles,wherein said compound or a pharmaceutically acceptable salt thereof isnot administered to the patient for a period of about 2 days to about 3days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

Further, the present invention includes a method of treating orpreventing a proliferative disorder in accordance with any otherembodiment disclosed above for the present invention.

In one embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is orally administered toa patient in need thereof in a daily dose of about 100 mg to about 450mg, preferably about 200 mg to about 400 mg or more preferably about 350mg to about 400 mg, of said compound of formula (I) or apharmaceutically acceptable salt thereof for at least twofive-consecutive day cycles, wherein said medicament is not administeredto the patient for a period of about 2 days to about 3 days between onefive-consecutive day cycle and its subsequent five-consecutive daycycle.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is orally administered toa patient in need thereof once per day (q.d.) in a daily dose of about100 mg to about 450 mg for at least two five-consecutive day cycles,wherein said compound or a pharmaceutically acceptable salt thereof isnot administered to the patient for a period of about 2 days to about 3days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is orally administered toa patient in need thereof twice per day (b.i.d.) in a daily dose ofabout 100 mg to about 450 mg for at least two five-consecutive daycycles, wherein said compound or a pharmaceutically acceptable saltthereof is not administered to the patient for a period of about 2 daysto about 3 days between one five-consecutive day cycle and itssubsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is orally administered toa patient in need thereof once per day (q.d.) in a daily dose of about100 mg to about 450 mg for at least two five-consecutive day cycles,wherein said compound or a pharmaceutically acceptable salt thereof isnot administered to the patient for a period of about 3 days between thelast administration of said compound or a pharmaceutically acceptablesalt thereof in one five-consecutive day cycle and the firstadministration of said compound or a pharmaceutically acceptable saltthereof in its subsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is orally administered toa patient in need thereof twice per day (b.i.d.) in a daily dose ofabout 100 mg to about 450 mg for at least two five-consecutive daycycles, wherein said compound or a pharmaceutically acceptable saltthereof is not administered for a period of about 2.5 days between thelast administration of said compound or a pharmaceutically acceptablesalt thereof in one five-consecutive day cycle and the firstadministration of said compound or a pharmaceutically acceptable saltthereof in its subsequent five-consecutive day cycle.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is orally administered inaccordance with the dosage regimen herein, wherein the compound offormula (I) or its pharmaceutically acceptable salt thereof isadministered in two or more of said five-consecutive day cycles untilthe relief, reduction, or alleviation of the severity, occurrence rate,or frequency of at least one side effect in said patient.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is orally administered inaccordance with the dosage regimen herein, wherein the compound offormula (I) or its pharmaceutically acceptable salt thereof isadministered in two or more of said five-consecutive day cycles untilthe progression of the disease.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease, wherein said medicament is first orallyadministered in amount of about 100 mg to about 450 mg daily dose on acontinuous daily schedule and subsequently reduced to an administeredamount of about 100 mg to about 450 mg daily dose for at least twofive-consecutive day cycles via oral administration, wherein saidcompound or a pharmaceutically acceptable salt thereof is notadministered to the patient for a period of about 2 days to about 3 daysbetween one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

Further, the present invention includes any use of the compound offormula (I) or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating or preventing a proliferativedisease in accordance with the methods of treatment or any embodimentdisclosed above for the present invention.

In one embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor treating or preventing a proliferative disease, wherein saidcompound of formula (I) or a pharmaceutically acceptable salt thereof isorally administered to a patient in need thereof in a daily dose ofabout 100 mg to about 450 mg for at least two five-consecutive daycycles, wherein said compound of formula (I) or a pharmaceuticallyacceptable salt thereof is not administered to the patient for a periodof about 2 days to about 3 days between one five-consecutive day cycleand its subsequent five-consecutive day cycle.

Further, the present invention includes any use of the compound offormula (I) or a pharmaceutically acceptable salt thereof in accordancewith the methods of treatment, uses for the manufacture of a medicament,or any embodiment disclosed above for the present invention.

The present invention further relates to a therapeutic regimencomprising orally administering a therapeutically effective amount ofthe compound of formula (I) or a pharmaceutically acceptable saltthereof to a patient in need thereof in a daily dose of about 100 mg toabout 450 mg for at least two five-consecutive day cycles, wherein saidcompound of formula (I) or a pharmaceutically acceptable salt thereof isnot administered to the patient for a period of about 2 days to about 3days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

The present invention further relates to the compound of formula (I) ora pharmaceutically acceptable salt thereof administered in combinationwith at least one additional therapeutic agent for the treatment orprevention of a proliferative disease, wherein the compound of formula(I) or a pharmaceutically acceptable salt thereof is administered in adaily dose of about 100 mg to about 450 mg for at least twofive-consecutive day cycles, wherein said compound of formula (I) or apharmaceutically acceptable salt thereof is not administered to thepatient for a period of about 2 days to about 3 days between onefive-consecutive day cycle and its subsequent five-consecutive daycycle.

Suitable therapeutic agents for use in accordance with the presentinvention include, but are not limited to, kinase inhibitors,anti-estrogens, anti androgens, other inhibitors, cancerchemotherapeutic drugs, alkylating agents, chelating agents, biologicalresponse modifiers, cancer vaccines, agents for antisense therapy.Examples are set forth below:

A. Kinase Inhibitors including inhibitors of Epidermal Growth FactorReceptor (EGFR) kinases such as small molecule quinazolines, for examplegefitinib (U.S. Pat. No. 5,457,105, U.S. Pat. No. 5,616,582, and U.S.Pat. No. 5,770,599), ZD-6474 (WO 01/32651), erlotinib (Tarceva®, U.S.Pat. No. 5,747,498 and WO 96/30347), and lapatinib (U.S. Pat. No.6,727,256 and WO 02/02552), and cetuximab; Vascular Endothelial GrowthFactor Receptor (VEGFR) kinase inhibitors, including SU-11248 (WO01/60814), SU 5416 (U.S. Pat. No. 5,883,113 and WO 99/61422), SU 6668(U.S. Pat. No. 5,883,113 and WO 99/61422), CHIR-258 (U.S. Pat. No.6,605,617 and U.S. Pat. No. 6,774,237), vatalanib or PTK-787 (U.S. Pat.No. 6,258,812), VEGF-Trap (WO 02/57423), B43-Genistein (WO-09606116),fenretinide (retinoic acid p-hydroxyphenylamine) (U.S. Pat. No.4,323,581), IM-862 (WO 02/62826), bevacizumab or Avastin® (WO 94/10202),KRN-951, 3-[5-(methylsulfonylpiperadine methyl)-indolyl]-quinolone,AG-13736 and AG-13925, pyrrolo[2,1-f][1,2,4]triazines, ZK-304709,Veglin®, VMDA-3601, EG-004, CEP-701 (U.S. Pat. No. 5,621,100), Cand5 (WO04/09769); Erb2 tyrosine kinase inhibitors such as pertuzumab (WO01/00245), trastuzumab, and rituximab; Akt protein kinase inhibitors,such as RX-0201; Protein Kinase C (PKC) inhibitors, such as LY-317615(WO 95/17182), and perifosine (US 2003171303); Raf/Map/MEK/Ras kinaseinhibitors including sorafenib (BAY 43-9006), ARQ-350RP, LErafAON,BMS-354825 AMG-548, MEK162, and others disclosed in WO 03/82272;Fibroblast Growth Factor Receptor (FGFR) kinase inhibitors; CellDependent Kinase (CDK) inhibitors, including CYC-202 or roscovitine (WO97/20842 and WO 99/02162); Platelet-Derived Growth Factor Receptor(PDGFR) kinase inhibitors such as CHIR-258, 3G3 mAb, AG-13736, SU-11248and SU6668; and Bcr-Abl kinase inhibitors and fusion proteins such asSTI-571 or Gleevec® (imatinib).

B. Anti-Estrogens: Estrogen-targeting agents include Selective EstrogenReceptor Modulators (SERMs) including tamoxifen, toremifene, raloxifene;aromatase inhibitors including Arimidex® or anastrozole; EstrogenReceptor Downregulators (ERDs) including Faslodex® or fulvestrant.

C. Anti-Androgens: Androgen-targeting agents including flutamide,bicalutamide, finasteride, aminoglutethamide, ketoconazole, andcorticosteroids.

D. Other Inhibitors including Protein farnesyl transferase inhibitorsincluding tipifarnib or R-115777 (US 2003134846 and WO 97/21701),BMS-214662, AZD-3409, and FTI-277; topoisomerase inhibitors includingmerbarone and diflomotecan (BN-80915); mitotic kinesin spindle protein(KSP) inhibitors including SB-743921 and MKI-833; proteasome modulatorssuch as bortezomib or Velcade® (U.S. Pat. No. 5,780,454), XL-784;cyclooxygenase 2 (COX-2) inhibitors including non-steroidalantiinflammatory drugs I (NSAIDs); letrozole; exemestane; and eribulin.

E. Cancer Chemotherapeutic Drugs including anastrozole (Arimidex®),bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan(Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®),N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®),carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®),cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®),cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposomeinjection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin(Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®),daunorubicin citrate liposome injection (DaunoXome®), dexamethasone,docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®),etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil(Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine(difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®),ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®),leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine(Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®),mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin,polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate(Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine(Tirazone®), topotecan hydrochloride for injection (Hycamptin®),vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine(Navelbine®).

F. Alkylating Agents including VNP-40101M or cloretizine, oxaliplatin(U.S. Pat. No. 4,169,846, WO 03/24978 and WO 03/04505), glufosfamide,mafosfamide, etopophos (U.S. Pat. No. 5,041,424), prednimustine;treosulfan; busulfan; irofluven (acylfulvene); penclomedine;pyrazoloacridine (PD-115934); 06-benzylguanine; decitabine(5-aza-2-deoxycytidine); brostallicin; mitomycin C (MitoExtra); TLK-286(Telcyta®); temozolomide; trabectedin (U.S. Pat. No. 5,478,932); AP-5280(Platinate formulation of Cisplatin); porfiromycin; and clearazide(meclorethamine).

G. Chelating Agents including tetrathiomolybdate (WO 01/60814); RP-697;Chimeric T84.66 (cT84.66); gadofosveset (Vasovist®); deferoxamine; andbleomycin optionally in combination with electorporation (EPT).

H. Biological Response Modifiers, such as immune modulators, includingstaurosprine and macrocyclic analogs thereof, including UCN-01, CEP-701and midostaurin (see WO 02/30941, WO 97/07081, WO 89/07105, U.S. Pat.No. 5,621,100, WO 93/07153, WO 01/04125, WO 02/30941, WO 93/08809, WO94/06799, WO 00/27422, WO 96/13506 and WO 88/07045); squalamine (WO01/79255); DA-9601 (WO 98/04541 and U.S. Pat. No. 6,025,387);alemtuzumab; interferons (e.g. IFN-a, IFN-b etc.); interleukins,specifically IL-2 or aldesleukin as well as IL-1, IL-3, IL-4, IL-5,IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, and active biologicalvariants thereof having amino acid sequences greater than 70% of thenative human sequence; altretamine (Hexalen®); SU 101 or leflunomide (WO04/06834 and U.S. Pat. No. 6,331,555); imidazoquinolines such asresiquimod and imiquimod (U.S. Pat. Nos. 4,689,338, 5,389,640,5,268,376, 4,929,624, 5,266,575, 5,352,784, 5,494,916, 5,482,936,5,346,905, 5,395,937, 5,238,944, and 5,525,612); and SMIPs, includingbenzazoles, anthraquinones, thiosemicarbazones, and tryptanthrins (WO04/87153, WO 04/64759, and WO 04/60308).

I. Cancer Vaccines: Anticancer vaccines including Avicine® (TetrahedronLett. 26:2269-70 (1974)); oregovomab (OvaRex®); Theratope® (STn-KLH);Melanoma Vaccines; GI-4000 series (GI-4014, GI-4015, and GI-4016), whichare directed to five mutations in the Ras protein; GlioVax-1; MelaVax;Advexin® or INGN-201 (WO 95/12660); Sig/E7/LAMP-1, encoding HPV-16 E7;MAGE-3 Vaccine or M3TK (WO 94/05304); HER-2VAX; ACTIVE, which stimulatesT-cells specific for tumors; GM-CSF cancer vaccine; and Listeriamonocytogenes-based vaccines.

J. Antisense Therapy: Anticancer agents including antisensecompositions, such as AEG-35156 (GEM-640); AP-12009 and AP-11014(TGF-beta2-specific antisense oligonucleotides); AVI-4126; AVI-4557;AVI-4472; oblimersen (Genasense®); JFS2; aprinocarsen (WO 97/29780);GTI-2040 (R2 ribonucleotide reductase mRNA antisense oligo) (WO98/05769); GTI-2501 (WO 98/05769); liposome-encapsulated c-Raf antisenseoligodeoxynucleotides (LErafAON) (WO 98/43095); and Sirna-027(RNAi-based therapeutic targeting VEGFR-1 mRNA).

In one embodiment, the additional therapeutic agent is selected fromgefinitib, erlotinib, bevacizumab or Avastin®, pertuzumab, trastuzumab,MEK162, tamoxifen, fulvestrant, capecitabine, cisplatin, carboplatin,cetuximab, paclitaxel, temozolamide, letrozole, or exemestane.

The structure of the drug substances identified by code numbers, genericor trade names may be taken from the Internet, actual edition of thestandard compendium “The Merck Index” or from databases, e.g., PatentsInternational, e.g., IMS World Publications, or the publicationsmentioned above and below. The corresponding content thereof is herebyincorporated by reference.

The compound of formula (I) and the additional therapeutic agent may beadministered together in a single pharmaceutical composition, separatelyin two or more separate unit dosage forms, or sequentially. Thepharmaceutical composition or dosage unit form comprising the additionaltherapeutic agent may be prepared in a manner known per se and are thosesuitable for enteral, such as oral or rectal, topical, and parenteraladministration to subjects, including mammals (warm-blooded animals)such as humans.

In particular, a therapeutically effective amount of each of thetherapeutic agents may be administered simultaneously or sequentiallyand in any order, and the components may be administered separately oras a fixed combination. For example, the combination of the presentinvention may comprise: (i) administration of the first therapeuticagent (a) in free or pharmaceutically acceptable salt form; and (ii)administration of an therapeutic agent (b) in free or pharmaceuticallyacceptable salt form, simultaneously or sequentially in any order, injointly therapeutically effective amounts, preferably in synergisticallyeffective amounts, e.g., in daily or intermittent dosages correspondingto the amounts described herein. The individual therapeutic agents ofthe combination may be administered separately at different times duringthe course of therapy or concurrently in divided or single combinationforms.

“Synergy” or “synergistic” refers to the action of two therapeuticagents such as, for example, (a) a compound of formula (I) or apharmaceutically acceptable salt thereof and (b) an aromatase inhibitor,producing an effect, for example, slowing the symptomatic progression ofa cancer disease or disorder, particularly cancer, or symptoms thereof,which is greater than the simple addition of the effects of eachtherapeutic agent administered by themselves. A synergistic effect canbe calculated, for example, using suitable methods such as theSigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin.Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity(Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326(1926)) and the median-effect equation (Chou, T. C. and Talalay, P.,Adv. Enzyme Regul. 22: 27-55 (1984)). Each equation referred to abovecan be applied to experimental data to generate a corresponding graph toaid in assessing the effects of the therapeutic agent combination. Thecorresponding graphs associated with the equations referred to above arethe concentration-effect curve, isobologram curve and combination indexcurve, respectively. Synergy may be further shown by calculating thesynergy score of the combination according to methods known by one ofordinary skill.

The effective dosage of each of therapeutic agent (a) or therapeuticagent (b) employed in the combination may vary depending on theparticular compound or pharmaceutical composition employed, the mode ofadministration, the condition being treated, the severity of thecondition being treated. Thus, the dosage regimen of the combination isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound employed. A physician, clinician or veterinarian of ordinaryskill can readily determine and prescribe the effective amount of thetherapeutic agent required to prevent, counter or arrest the progress ofthe condition. Optimal precision in achieving concentration oftherapeutic agent within the range that yields efficacy requires aregimen based on the kinetics of the therapeutic agent's availability totarget sites. This involves a consideration of the distribution,equilibrium, and elimination of a therapeutic agent.

Examples of proliferative diseases that may be treated with acombination of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and at least one additional therapeutic agentinclude, but not limited to, those set forth above.

It can be shown by established test models that the combination of thepresent invention results in the beneficial effects described hereinbefore. The person skilled in the art is fully enabled to select arelevant test model to prove such beneficial effects. Thepharmacological activity of a combination of the present invention may,for example, be demonstrated in a clinical study or in a test procedureas essentially described hereinafter.

Suitable clinical studies are in particular, for example, open label,dose escalation studies in patients with a proliferative disease,including for example a tumor disease, e.g., breast cancer. Such studiesprove in particular the synergism of the therapeutic agents of thecombination of the present invention. The beneficial effects on aproliferative disease may be determined directly through the results ofthese studies which are known as such to a person skilled in the art.Such studies may be, in particular, suitable to compare the effects of amonotherapy using the therapeutic agents and a combination of thepresent invention. In one embodiment, the dose of the alpha-isoformselective PI3K inhibitor compound of formula (I) or its pharmaceuticallyacceptable salt is escalated until the Maximum Tolerated Dosage isreached, and the combination partner is administered with a fixed dose.Alternatively, the compound of formula (I) or its pharmaceuticallyacceptable salt may be administered in a fixed dose and the dose of thecombination partner may be escalated. Each patient may receive doses ofthe compound of formula (I) or its pharmaceutically acceptable salteither once per day or more than once (e.g., twice) per day. Theefficacy of the treatment may be determined in such studies, e.g., after12, 18 or 24 weeks by evaluation of symptom scores every 6 weeks.

In the combination of the present invention, the compound of formula (I)or a pharmaceutically acceptable salt thereof is administered in a dailydose of about 100 mg to about 450 mg for at least two five-consecutiveday cycles, wherein said compound of formula (I) or a pharmaceuticallyacceptable salt thereof is not administered to the patient for a periodof about 2 days to about 3 days between one five-consecutive day cycleand its subsequent five-consecutive day cycle.

In one embodiment, the present invention relates to a method of treatinga treating or preventing a proliferative disease by administration inaccordance with the dosage regimen of the present invention, whereinsaid compound of formula (I) or a pharmaceutically acceptable saltthereof is administered in combination with at least one additionaltherapeutic agent.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament for treating or preventing aproliferative disease in accordance with the dosage regimen of thepresent invention, wherein said compound of formula (I) or apharmaceutically acceptable salt thereof is administered in combinationwith at least one additional therapeutic agent.

In a further embodiment, the present invention relates to the use of thecompound of formula (I) or a pharmaceutically acceptable salt thereoffor treating or preventing a proliferative disease in accordance withthe dosage regimen of the present invention, wherein said compound offormula (I) or a pharmaceutically acceptable salt thereof isadministered in combination with at least one additional therapeuticagent.

The present invention further relates to a package comprising apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof in a daily dose of about 100 mgto about 450 mg together with one or more pharmaceutically acceptableexcipients in combination with instructions to orally administer saidpharmaceutical composition for at least two five-consecutive day cyclesand to not administered said composition for a period of about 2 days toabout 3 days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.

Utility of the dosage regimen of the compounds of formula (I) of thepresent invention may be demonstrated in vitro, in animal test methodsas well as in clinic studies. For example in the utility of thecompounds of formula (I) in accordance with the present invention may bedemonstrated in accordance with the methods hereinafter described:

Example 1 Materials and Methods

Animals and Maintenance Conditions:

Experiments were performed in female Hsd: Athymic Nude-nu CPB mice(Harlan Winkelmann, Germany). Animals were between 12 and 14 weeks ofage at treatment start and housed under Optimized Hygienic Conditions(OHC) in Makrolon type III cages (max. 5 animals per cage) with freeaccess to food and water. In addition, experiments were also performedin female nude Rowett rats Hsd: RH-Fox1rnu (Harlan (The Netherlands).Animals were 6-9 weeks of age at time of application of the compound.Animals were housed under Optimized Hygienic Conditions in Makrolon typeIII cages (max. 2 animals per cage) with free access to food and water.They were allowed to adapt for at least 6 days before the experiment wasstarted.

Cell Line and Cell Culture:

Rat1-Myr-p110α cells were grown in Dulbecco's Modified Eagle Medium(DMEM) culture medium containing 4.5 g/l glucose supplemented with 10%heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine, 1 mM sodiumpyruvate and incubated at 37° C. in a 5% CO₂ humidified atmosphere.Cells were harvested with trypsin-EDTA, re-suspended in culture medium(with additives) and counted with a Casy® system. Finally, cells arecentrifuged, suspended in ice-cold Hanks' balanced salt solution (HBSS)at a concentration of 3×10⁷ cells/ml. Cell culture reagents werepurchased from BioConcept (Allschwil, Switzerland).

Rat1-myr-p110α cells were generated by the method described in Maira etal., Molecular Cancer Therapeutics, 11:317-328 (2012), which isincorporated herein by reference in its entirety. Briefly, Rat1 cellswere transfected to stably express the constitutively active form of thecatalytic PI3K class I p110 isoforms a by addition of a myristylationsignal to the N-terminus.

Establishment of Tumor Xenografts In Vivo:

Rat1-Myr-p110α tumors were established by subcutaneous injection of5×10⁶ cells in 100 μL HBSS (Sigma #H8264) into the right flank of nudemice or nude rats. For the efficacy experiments, treatments wereinitiated when the mean tumor volumes were approx. 300 mm³ (14 to 15days post tumor cells injection). For single dose PK/PD experiments,animals were treated once orally with Compound A when the tumors reacheda size of approx. 400-500 mm³ (21 to 23 days post tumor cellsinjection).

Compound Formulation and Animal Treatment:

Compound A was prepared for dosing as homogenous suspensions in 1%carboxymethyl cellulose: 0.5% Tween® 80: 98.5% deionized water. Freshsuspensions were prepared once every 4 days and stored at 4° C. CompoundA or vehicle was administered orally at a volume of 10 mL/kg.

Evaluation of Antitumor Activity:

Tumor volumes were measured with calipers and determined according tothe formula: length×diameter²×π/6. In addition to presenting changes oftumor volumes over the course of treatments, antitumor activity isexpressed as T/C % (mean change of tumor volume of treated animals/meanchange of tumor volume of control animals)×100. Regressions (%) werecalculated according to the formula ((mean tumor volume at end oftreatment−mean tumor volume at start of treatment)/mean tumor volume atstart of treatment)×100. Body weights and tumor volumes were recordedtwo to three times a week.

Sampling:

Blood samples were collected at different time points post the lasttreatment (1 hour, 2 hour, 4 hour, 8 hour, 12 hour, 16 hour and 24 hour,n=2-3 per time point) into tubes coated with K-EDTA. Blood samples werecentrifuged and collected plasma immediately frozen at −80° C. untilfinal processing. Tumors were collected at sacrifice at 7 time points (1hour, 2 hour, 4 hour, 8 hour, 12 hour, 16 hour and 24 hour, n=2-3 pertime point), snap frozen and kept at −80° C. until final processing.

Pharmacokinetic/Pharmacodynamic Analyses

A. Animal Tissue Pulverization:

After dissection, the tumors were snap-frozen in liquid nitrogen andstored at −80° C. Frozen tumors were pulverized using a Retsch ballmixer mill MM20 (Arlesheim, Switzerland) with metal cylinders that werepre-cooled to −80° C. in a freezer. Powder was scrapped from metalcylinders on dry ice and transferred into pre-cooled 1.5 mL Eppendorftubes while avoiding melting.

B. Bioanalytics (LC/MS-MS) for Quantification of Compound A:

Concentrations of Compound A in plasma and tumor were determined in aseparate run by using ultra-high-pressure liquid chromatography/tandemmass spectrometry (UPLC/MS-MS). Following addition of 25 μL of internalstandard (1 μg/mL) to analytical aliquots (25 μL) of plasma or (20 mg)tumor powder, the proteins were precipitated by the addition of 200 μLacetonitrile. The supernatant were transferred in a fresh vial. Afterevaporation to dryness the samples were re-dissolved in 60 μLacetonitrile/water (1/1 v/v). An aliquot (5 μL) of this solution wasseparated on a ACQUITY UPLC BEH C18 column (Waters™ 1.7 μm particlesize, 2.1×50 mm) with a mobile phase consisting of a mixture of 0.1%formic acid in water (solvent A) and 0.1% formic acid in acetonitrile(solvent B). Gradient programming was used with a flow rate of 600μL/min. After equilibration with 95% solvent A, 5 μL of sample wasinjected. Following a latency period of 0.25 min, the sample was elutedwith a linear gradient of 5-100% solvent B over a period of 0.65 minutesfollowed by a 0.35 minutes hold. The column was prepared for the nextsample by re-equilibrating over 0.25 minutes to the starting conditions.The column eluent was directly introduced into the ion source of thetriple quadrupole mass spectrometer TQD™ (Waters Corporation, Milford,Mass., USA) controlled by Masslynx™ 4.1 software. Electrospray positiveionization (ESI+) multiple reaction monitoring was used for the MS/MSdetection of the analyte. Precursor to product ion transitions forCompound A and the corresponding internal standard are summarized in thefollowing Table:

Precursor Product Precursor Product ion ion Internal ion ion [m/z] [m/z]standard [m/z] [m/z] Compound A 442.10 328.10 Compound B 387.10 273.10The limit of quantification (LOQ) for Compound A was set to 2.5 ng/mL(CV and overall bias less than 30%). Regression analysis and furthercalculations were performed using QuanLynx™ 4.1 (Micromass) and Excel™2007 (Microsoft). Concentrations of unknown samples were back-calculatedbased on the peak area ratios of analyte/IS from a calibration curveconstructed using calibration samples spiked in blank plasma or tumorobtained from animals treated with vehicle.

C. Quantification of Ser473 P-Akt and Akt Via Reverse Phase ProteinArray (RPPA) Approach.

Approximately 20 mg of frozen tissue powder was weighed out and lyzed in100 μL NP40 protein lysis buffer mix (Lysis buffer stock (4° C.): 2.5 mLTris HCL 2M pH 7.8 RT, 1 mL NP40 (100%) RT, 2.4 mL NaCl 5M RT, 2.5 mLNaF 1M RT, 4 mL 1M beta glycerol phosphate disodium salt penthahydrate−20° C., and water till 100 mL; Lysis buffer solution (4° C.): 10 mLlysis buffer stock; 10 uL Na3VO3 100 mM 4° C., 10 uL DTT 1M −20° C., 10uL PMSF 100 mM 4° C., 10 uL Benzamidine 1M −20° C., and 10 uLMicrocystin −20° C.).

Each sample was vortexed and centrifuged for 10 minutes at 10,000 rpm. Afreezing thawing cycle was performed at −80° C. for 30 minutes. Thesamples were stored, after an additional centrifugation step at 10 000rpm for 10 minutes, at −80° C. for further analysis. The proteinconcentrations were quantified using the Coomassie Plus Kit (#23236Thermo Scientific, Rockford, Ill., USA) according to the protocol of themanufacturer. The diluted samples were transferred into a 96 well plate(#269620, NUNC) and the absorbance was measured at 595 nm using aSpectraMAX Plus plate reader from Molecular Devices. The Protein amountwas calculated using the Softmax Pro 5.0 software (Molecular Devices,USA) and then normalized on 1 mg/mL using the corresponding lysisbuffer. The normalized samples were further diluted 1:10 using the CSBL1CeLyA spotting buffer (Zeptosens, cat. No. 9020) supplemented with 1 mMNa-orthovanadate (Sigma, cat No. S-6508). The lysate was transferred toa 96-well V-bottom plate (Fisher Scientific, cat. No. 6067Y), followedby a centrifugation step (5 min, 1500 rpm at 19° C. in an Eppendorf5810R centrifuge) to remove the unlyzed cell debris.

A MATRIX 2×2 automated pipetting workstation (Thermo Fisher Scientific,UK) was used for reformatting the lysates from the 96-well V-bottomplates to 384-well plates (Greiner, cat. No. 781201). To obtain thedesired spotting layout, every sample was diluted to 4 different sampleconcentrations (d1=100%, d2=75%, d3=50%, d4=25%) by diluting the celllysate with the corresponding volume of lysis-spotting buffer mix (10%lysis buffer; 90% CSBL1 spotting buffer supplemented with 1 mMNa-orthovanadate.

The samples were spotted onto ZeptoMARK@ PWG protein microarray chips(Zeptosens, Witterswil, Switzerland) with the piezoelectricmicrodispense-based, non-contact Nano-Plotter 2.1 (GeSiM,Grosserkmannsdorf, Germany). Each sample was spotted at 4 differentsample concentrations (d1=100%, d2=75%, d3=50%, d4=25%) by diluting thecell lysate with the corresponding volume of spotting-lysis buffer mix.After spotting the ZeptoMARK® protein microarrays, the chips areincubated for 1 hour at 37° C. To receive a uniform blocking result, theCeLyA blocking buffer BB1 (Zeptosens, cat. No. 9040) is administered viaan ultrasonic nebulizer. After 20 minutes of blocking the chips areextensively rinsed with deionized water (Milli-Q quality, 18M′Ω×cm) anddried in a nitrogen air flow.

Then, the ZeptoMARK® chips were transferred to the ZeptoCARRIER(Zeptosens, cat. No. 1100), and washed twice with 200 μL CAB1 CeLyAassay buffer (Zeptosens, cat. No. 9032). The assay buffer was thenaspirated and each compartment incubated with 100 μL of the primarytarget antibody (pAkt Ser473 (lot no. 9)(Cell Signaling Technology,Catalog No. 4060); Akt1 pan (lot no. E0401) (Epitomics, Catalog No.1085-1); Zenon® Alexa Fluor 647 rabbit (Invitrogen, Catalog No. Z25308))at room temperature (RT) overnight. Post incubation, the primaryantibody was removed, the arrays washed twice with CAB1 buffer andfurther incubated with 100 μL of Alexa fluor 647-labeled anti rabbit IgGFab fragments (Invitrogen; #Z25305) for one hour at RT in the dark.After incubation, the arrays were washed twice with 200 μL CAB1 buffer.The fluorescence of the target-bound Fab fragments was read out on theZeptoReader (Zeptosens, Witterswil, Switzerland) using a laser(excitation wavelength 635 nm) and a CCD camera. The fluorescence signalwas assessed with exposure times of 1, 3, 5 and 10 seconds, depending onthe intensity of the signal. The fluorescence images for each array wereanalyzed with the ZeptoVIEW Pro 2.0 software (Zeptosens, Witterswil,Switzerland) and the RFI (relative fluorescence intensity) for eachsignal was calculated.

D. PK-PD Modeling:

Phoenix WinNonlin 6.3 (Pharsight) was used to simulate the mean plasmaconcentration time profiles after multiple dosing using thenon-compartmental nonparametric superposition approach of data generatedeither from a mouse or rat efficacy study. The predictions are basedupon an accumulation ratio computed from the terminal slope (Lambda Z),allowing predictions from simple or complicated dosing schedules.

Statistical Analysis:

Absolute values for primary tumor growth and body weight were used tomake the statistical comparisons between groups (one way ANOVA followedby Dunnett's test for normally distributed data; ANOVA on Ranks for notnormally distributed data followed by Dunnett's test for equal groupsize or Dunn's for unequal group size). The significant level was set atp<0.05. Areas under the curve (AUC) recorded for 24 h post lasttreatment was determined by using the trapezoidal rule method. Allstatistical calculations were carried out using SigmaStat.

Results

The pre-clinical PK-PD-Efficacy-Tolerability model for Compound A wasestablished following the methods set forth above. For this pre-clinicalPK-PD-Efficacy-Tolerability model for Compound A:

Pharmacokinetic Studies and PK Modeling for Compound A:

The pharmacokinetics of Compound A were linear over the range of dosestested (FIG. 1 A: 12.5, 25 and 50 mg/kg qd in nude mice; FIG. 1 B: 12.5,25, 40 and 80 mg/kg qd in nude rats), and associated with a similarchange in AUC between 12.5 and 50 mg/kg in nude mice. A similarrelationship was observed in nude rats for doses up to 80 mg/kg. FIGS.2A and 2B provides a non-parametric superposition model to show therelationship of observed vs. predicted plasma concentrations after oraladministration of Compound A at 50 mg/kg qd in nude mice and 40 mg/kg qdin nude rats. (FIGS. 2 A and B). FIGS. 3 A and B provides a comparisonof the observed plasma concentrations and model predictions andindicates that this PK model used is very predictive in nude mice(R²=0.99, n=25, p<0.001) at doses below 150 mg/kg qd and nude rats(R²=0.89, n=31, p<0.01) at doses below 100 mg/kg qd. Moreover, FIG. 4Aindicates that this PK model used is also predictive to simulate PKprofiles Compound A given twice a day (2 qd) in nude mice.

This PK modeling study was repeated to confirm the prior finding thatthis PK model is predictive to simulate PK profiles of Compound A giventwice a day (2 qd) in nude mice. The results of this repeat study areprovided in FIG. 4B and re-confirm that this PK model is predictive tosimulate PK profiles for Compound A given twice a day (2 qd) in nudemice. This FIG. 4B data is provided herein solely to demonstrate furtherconfirmation of the PK modeling study in nude mice.

PK-PD-Efficacy Modeling

A. Modulation of Phosphorylation of Akt:

The tumor concentrations giving 50% (in vivo IC₅₀) and 80% (in vivoIC₈₀) S473P-Akt inhibition (0.6 and 4 μmol/L, respectively) versuscontrols were determined by measuring the level of Akt phosphorylationusing RPPA and the specific tumor drug concentration in matched samplesfrom multiple animals (nude mice and rats) and at multiple time pointspost-treatment with Compound A (FIG. 5). When corrected for plasmaprotein binding of Compound A in mouse (PPB=91.2%), the in vivo IC₅₀ (53nmol/L) and IC₈₀ (352 nmol/L) values roughly approximate the in vitrocellular IC₅₀ and IC₈₀ of 74 nmol/L and 301 nmol/L respectively.

B. Antitumor Activity of Compound a in the Rat1-Myr-p110α Tumor Model:

Compound A was administered orally to Rat1-myr-p110α tumor bearing miceand rats at various doses. Tumor growth inhibition results aresummarized below:

Efficacy Efficacy T/C Regres- T/C Regres- Nude Mice - (ob- sion (ob-Nude Rat (ob- sion (ob- Dose served) served) Dose served) served) 6.25mg qd  0.19 — 6.25 mg qd 0.22 — 12.5 mg qd  0.09 — 12.5 mg qd 0.05 —  25mg qd — −0.53  25 mg qd — −0.65  50 mg qd — −0.65  50 mg qd — −0.80 6.25mg 2qd 0.02 — 12.5 mg 2qd — −0.55  20 mg 2qd — −0.80  40 mg 2qd — −0.86The inhibition appeared to be dose-dependent. Tumor regression wasobserved at daily doses higher than 25 mg/kg in nude mice and rats andtwice-daily doses higher than 12.5 mg/kg in nude mice.

C. PK/PD/Efficacy Relationship:

FIG. 6 provides the relationship between exposure (as measured by timeover the in vivo IC80) and anti-tumor efficacy. Further, a nearly linearrelationship is identified between the anti-tumor efficacy magnitude andduration of drug exposure (as measured by time over the in vivo IC₈₀)over the IC₈₀ (R²=0.89; FIG. 7). From this relationship, it has beendetermined that 80% inhibition of Akt phosphorylation for at least 25%of the dosing interval is required for Compound A to induce tumorstasis, and that this level of pathway inhibition must be sustained forat least 45% of the dosing interval to produce 30% tumor regression.

FIG. 8 provides a comparison of observed tumor growth inhibition and themodel prediction tumor growth inhibition after oral administration ofCompound A from 6.25 to 70 mg/kg in qd and 2 qd dosing. Thus, this PK/PDrelationship model is predictive of antitumor efficacy of alternativedosing regimens in mice and rats treated orally with various doses ofCompound A (R²=0.93, n=12, p<0.001).

PK-PD-Tolerability Modeling

A. Modulation of Glucose and Insulin Levels:

To assess whether Compound A perturbs glucose homeostasis, plasmainsulin and glucose blood levels were measured and compared with plasmadrug concentrations in matched samples from multiple animals and atmultiple time points. In this analysis, insulin plasma levels increasedproportionally with Compound A plasma concentrations, while bloodglucose levels were maintained close to normal up to 20 μmol/L ofCompound A in nude mice (FIGS. 9 A and B) and up to 15 μmol/L ofCompound A in nude rats (FIGS. 10 A and B). However, above 20 μmol/L innude mice and 15 μmol/L in nude rats, a compound concentration-dependentglucose increase which led to hyperglycemia was observed despite insulinplasma level elevation. Thus, the Compound A—related hyperglycemicthreshold was defined to be 20 μmol/L and 15 μmol/L in mice and rats,respectively.

B. PK/PD/Tolerability Relationship:

Further, a nearly linear relationship was observed between the bodyweight loss magnitude and duration of exposure above Compound Ahyperglycemia threshold (20 μmol/L for nude mice and 15 μmol/L for nuderats; R²=0.98, FIG. 11). From this relationship, it is understood thatthe compound exposure levels should be sustained for no more than 35% ofthe dosing interval above the hyperglycemia cut-off to maintain bodyweight loss below 5% in mice and rats.

PK-PD-Efficacy Modeling

Simulated efficacy curves (as determined by the fraction of time abovethe IC₈₀ threshold for S473P-Akt) and tolerability curves (as determinedby the duration of exposure above Compound A hyperglycemia threshold (20μmol/L)) in mice treated orally qd with increasing doses of Compound Aare shown in the graph at FIG. 12. The modeling suggests that at thedose of 70 mg/kg qd (less than 5% BW loss), 80% pAkt inhibition will beachieved for 65% of the time between two consecutive treatments leadingto 55% tumor regression (FIG. 12, FIG. 7). If the dose of 70 mg/kg qd isgiven as 35 mg/kg twice a day (2 qd), the model tells us that 80% pAktinhibition will be achieved for 100% of the time between two consecutivetreatments leading to tumor regression. In nude rats were thehyperglycemia threshold was set to 15 μmol/L, the dose of 30 mg/kg qd(no BW loss) will lead to 80% pAkt inhibition for 83% of the timebetween two consecutive treatments leading to 80% tumor regression (FIG.13, FIG. 7).

Case Study: 20 mg/kg Qd in “ALTERNATIVE SCHEDULE 1” Dosing Regimen inNude Rats

Based upon the foregoing analysis, the pre-clinicalPK-PD-Efficacy-Tolerability modeling for Compound A described above is avaluable tool to predict efficacy and tolerability of the followingdosing schedule of Compound A: oral administration of Compound A onceper day (q.d.) or twice per day (b.i.d.) for five-consecutive daysfollowed by no administration of Compound A for two days (CYCLE 1), andthen a repeat of the same dosing regimen [i.e, oral administration ofCompound A once per day (q.d.) or twice per day (b.i.d.) forfive-consecutive days, followed by no administration of Compound A fortwo days] in one or more subsequent cycles. This alternative dosingschedule is referred to as “ALTERNATIVE SCHEDULE 1”. As describedherein, this model is here used to explore and guide dose scheduling inclinical studies.

FIG. 14 provides graphs showing the simulated efficacy of Compound A inRat1-myr P110α tumor bearing nude rats orally with COMPOUND A at 20mg/kg in ALTERNATIVE SCHEDULE 1 (A) as compared to 14 mg/kg qd incontinuous daily schedule (ie., with no drug holiday) (B). FIG. 15provides the simulated plasma PK profile in Rat1-myr P110α tumor bearingnude rats orally with COMPOUND A at 20 mg/kg in ALTERNATIVE SCHEDULE 1as compared to 14 mg/kg qd in continuous daily schedule (ie., with nodrug holiday).

Based on our model simulation (FIG. 7), ALTERNATIVE SCHEDULE 1 forCompound A can (a) achieve similar or improved anti-tumor efficacyobserved in nude rats orally administered Compound A once each day(q.d.) on a continuous daily schedule and (b) achieve at least partialregression (30% tumor regression) over the entire treatment period ifCompound A plasma concentration is above the IC₈₀ on pAkt for 45% of thetime between two treatment periods. Based on equivalent AUC, the humandose for Compound A of 300-350 mg/day p.o. (Cmax: 3500 ng/ml=8 μmol/L;AUC: 35000 h·ng/ml=80 h·μmol/L) corresponds to a 20 mg/kg ALTERNATIVESCHEDULE 1 p.o. dose in nude rats. The corresponding total dose for qdin continuous daily schedule p.o. dose would be 14 mg/kg.

According to this model in nude rats (FIG. 13), Compound A at 20 mg/kgwill result in approximately 60% tumor regression. Thus, predictedefficacy of 20 mg/kg in ALTERNATIVE SCHEDULE 1 in nude rats is presentedin FIG. 14 A. Max efficacy is 60% regression with a recovery to 30%regression at the end of the 2 days of drug holidays. Predicted efficacyfor the 14 mg/kg daily dosing is continuous 30% tumor regression (FIG.14 B).

The predicted Compound A plasma levels following oral treatment in miceand rats with 14 mg qd in continuous daily schedule or 20 mg inALTERNATIVE SCHEDULE 1 will not exceed 15 μmol (Hyperglycemiathreshold). (FIG. 15)

Assuming that the relationship between PD and efficacy is similar inhumans and xenografts, this model and analysis may be useful to predicttumor response in humans to ALTERNATIVE SCHEDULE 1.

1. A method of treating or preventing a proliferative disease in apatient in need thereof, comprising orally administering atherapeutically effective amount of the compound of formula (I)

or a pharmaceutically acceptable salt thereof to the patient in a dailydose of about 100 mg to about 450 mg for at least two five-consecutiveday cycles, wherein said compound or a pharmaceutically acceptable saltthereof is not administered to the patient for a period of about 2 daysto about 3 days between one five-consecutive day cycle and itssubsequent five-consecutive day cycle.
 2. A method of treating orpreventing a proliferative disease comprising first administering to apatient in need thereof a compound of formula (I) according to claim 1or a pharmaceutically acceptable salt thereof in amount of about 100 mgto about 450 mg daily on a continuous daily schedule via oraladministration, second determining said patient has a side effectselected from neutropenia, elevated bilirubin, cardiac toxicity,unstable angina, myocardial infarction, persistent hypertension,peripheral sensory or motor neuropathy/pain, hepatic dysfunction,reduced red and/or white blood cell count, hyperglycemia, nausea,decreased appetite, diarrhea, rash and hypersensitivity,photosensitivity, asthenia/fatigue, vomiting, stomatitis, oralmucositis, pancreatitis, dysgeusia, and dyspepsia after administrationof said compound of formula (I) or a pharmaceutically acceptable saltthereof to said patient, and third reducing the administration of saidcompound of formula (I) or a pharmaceutically acceptable salt thereof toa daily dose of about 100 mg to about 450 mg via oral administration forat least two five-consecutive day cycles via oral administration,wherein said compound or a pharmaceutically acceptable salt thereof isnot administered to the patient for a period of about 2 days to about 3days between one five-consecutive day cycle and its subsequentfive-consecutive day cycle.
 3. (canceled)
 4. A method according to claim1, wherein the daily dose of the compound of formula (I) or apharmaceutically acceptable salt thereof is about 200 mg to about 400mg.
 5. A method according to claim 1, wherein the compound of formula(I) or a pharmaceutically acceptable salt is orally administered onceper day (q.d.) in a daily dose of about 100 mg to about 450 mg for atleast two five-consecutive day cycles.
 6. A method according to claim 1,wherein the compound of formula (I) or a pharmaceutically acceptablesalt is orally administered twice per day (b.i.d) in a daily dose ofabout 100 mg to about 450 mg for at least two five-consecutive daycycles.
 7. A method according to any one of claims 1 to 6, wherein saidcompound or a pharmaceutically acceptable salt thereof is notadministered to the patient for a period of about 2 days between onefive-consecutive day cycle and its subsequent five-consecutive daycycle.
 8. A method according to claim 5, wherein said compound or apharmaceutically acceptable salt thereof is not administered to thepatient for a period of about 3 days between the last administration ofsaid compound or a pharmaceutically acceptable salt thereof in onefive-consecutive day cycle and the first administration of said compoundor a pharmaceutically acceptable salt thereof in its subsequentfive-consecutive day cycle.
 9. A method according to claim 6, whereinsaid compound or a pharmaceutically acceptable salt thereof is notadministered to the patient for a period of about 2.5 days between thelast administration of said compound or a pharmaceutically acceptablesalt thereof in one five-consecutive day cycle and the firstadministration of said compound or a pharmaceutically acceptable saltthereof in its subsequent five-consecutive day cycle.
 10. A methodaccording to claim 1, wherein the compound of formula (I) or apharmaceutically acceptable salt thereof is administered in two or moreof said five-consecutive day cycles until the relief, reduction, oralleviation of the severity, occurrence rate, or frequency of at leastone side effect in said patient.
 11. A method according to claim 10,wherein the side effect is a condition selected from neutropenia,elevated bilirubin, cardiac toxicity, unstable angina, myocardialinfarction, persistent hypertension, peripheral sensory or motorneuropathy/pain, hepatic dysfunction, reduced red and/or white bloodcell count, hyperglycemia, nausea, decreased appetite, diarrhea, rash(e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g.,increased sensitivity to bruise), photosensitivity, asthenia/fatigue,vomiting, stomatitis, oral mucositis, pancreatitis, dysgeusia, anddyspepsia.
 12. A method according to claim 1, wherein the proliferativedisease is a cancer.
 13. A method according to claim 1, wherein theproliferative disease is a cancer selected from a cancer of the lung,bronchus, prostate, breast (including sporadic breast cancers andsufferers of Cowden disease), colon, rectum, colon carcinoma, colorectaladenoma, pancreas, gastrointestine, hepatocellular, stomach, gastric,ovary, squamous cell carcinoma, and head and neck.
 14. A methodaccording to claim 1, wherein the compound of formula (I) or apharmaceutically acceptable salt thereof is administered in combinationwith at least one additional therapeutic agent.
 15. (canceled)
 16. Apackage comprising a pharmaceutical composition comprising a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof in a daily dose of about 100 mg to about 450 mg together withone or more pharmaceutically acceptable excipients in combination withinstructions to orally administer said pharmaceutical composition for atleast two five-consecutive day cycles and to not administered saidcomposition for a period of about 2 days to about 3 days between onefive-consecutive day cycle and its subsequent five-consecutive daycycle.